Introduction to Tumour Suppressor genes Flashcards
(34 cards)
What do tumour suppressor genes (TSGs) do?
- Encode proteins that maintain checkpoints in the cell cycle and to control genome stability
- Inhibit replication and proliferation of damaged cells
How do TSGs carry out their function
- DNA damage repair
- Apoptosis
Which TSGs carry out DNA damage repair?
- MLH1
- BRCA1/2
Which TSG carries out apoptosis?
TP53
When and who discovered TSGs?
Henry Harris in 1969 through somatic cell hybridisation
When was the first TSG identified?
- In 1986, the RB1 gene was identified
- It causes retinoblastoma and it is a dominant gene
What is the Knudson’s two-hit hypothesis in TSG inactivation?
- Discovered by Alfred Knudson in 1971
- Most loss-of-function mutations that occur in TSGs are recessive
- This is because typically, one normal allele is sufficient for cellular control
- This means that both copies on the homologous TSG need to be mutated in order for cancer to occur
How does TSG inactivation occur for heritable genes?
- In a normal cell, there needs to be 2 mutations to lead to cancer
- In a germline cell, there is already 1 mutation which is inherited, therefore only 1 more mutation needs to occur to lead to cancer
What are mutations in both alleles called?
Loss of heterozygosity
What are 4 functions of TSGs?
- Act as oncogene antagonists
- Block cell proliferation (through cell cycle inhibitors and activation/repression of transcription factors
- Induce apoptosis
- DNA repair
What do DNA repair genes do?
- Encode DNA repair enzymes which continuously monitor chromosomes to detect any damage caused by carcinogens or errors in DNA replication
What is an example of damage that DNA repair enzymes fix?
- Double strand breaks caused by ionising radiation
- Repaired by homologous recombination
What is the effect if the DNA repair gene loses function?
- Loss of gene results in acquisition of more mutations
- Defect of gene results in genomic instability and the acceleration in activation of oncogenes and loss of TSGs
- Tumours arising in patients as a result of inherited defects in DNA repair genes tend to have a very high mutational load
What are the BRCA1/2 genes?
- DNA repair genes that encode proteins that repair DNA double strand breaks through homologous recombination
Which cancers do BRCA1/2 increase the risk of?
- Female/Male breast cancer
- Ovarian cancer
- Melanoma
- Prostate cancer
- Pancreatic cancer
How are single strand breaks repaired by BRCA1/2?
They undergo base excision repair (BER) using the enzyme poly ADP-ribose polymerase (PARP)
What is synthetic lethality?
- Occurs when the inhibition of two genes is lethal while the inhibition of each single gene is no
- Can be harnessed to selectively treat cancer by identifying inactive genes in a given cancer and targeting their synthetic lethal partners.
How does synthetic lethality work to treat BRCA1/2 mutations in cancer?
- PARP inhibitors are used to inhibit PARP1 which results in an accumulation of single strand breaks
- This accumulation also leads to an accumulation in double strand breaks
- This draws the BRCA mutated cells to the site
- However, because they are mutated they’re unable to repair so the cell dies
- This stops cell growth and therefore tumour growth
What are 4 examples of PARP inhibitors?
- Olaparib
- Rucaparib
- Niraparib
- Talazoparib
What does the TP53 gene do?
Produces p53 protein
What does p53 protein do?
- Acts as tumour suppressor to regulate cell division so there is no unregulated growth
- Located in cytoplasm and nucleus and binds to DNA
- Detects cellular stress and DNA damage and either signals for repair or apoptosis depending on the state of the cell
Why is p53 referred to as ‘Guardian of the Genome’
It regulates cell division so no uncontrolled cell growth occurs therefore no tumours form
Why are the levels of p53 low in normal cells?
The levels are low so they can be tightly regulated, if they were high, it is possible that they could work too much which would lead to excess apoptosis which could result in tissue damage
How is p53 regulated?
- It is regulated by MDM2 gene which produces MDM2 protein and binds to p53
- This forms a complex which targets p53 to destruction in lysosomes
- This allows p53 to work via negative feedback
